Neuropeptide-receptors complex are often deregulated during the neoplastic process. Several concomitant and well described oncogenic pathways are engaged by these complexes, caused by abnormal autocrine or paracrine regulation, and resulting in the enhancement of cancer progression (Heasley L E. Oncogene 20(13):1563-9, 2001). Amongst these complexes involved in cancer progression is the 13 amino acid Neurotensin (NTS) and its cognate high affinity neurotensin receptor 1 (NTRS1). NTS, which is mainly localized in the gastrointestinal tract, participates in local physiological functions by modulating the release of major substances, such as pancreatic and biliary secretions, substance P, prostaglandin, and others. NTSR1 expression is found in human tumors deriving mainly from epithelial origin, such as the colon, pancreas, prostate, and breast (Evers B M. Peptides 27(10):2424-33 2006; Souaze F et al, Cancer Res 66(12):6243-9 2006).
NTSR1 expression is minimally present or absent in normal epithelial cells. However, it is induced in the early stages of carcinogenesis by the activation of the Wnt/beta catenin pathway (Elek J et al. Anticancer Res 20(1A):53-8, 2000; Souaze F et al. Carcinogenesis 27(4):708-16, 2006). The activation of NTSR1 leads to cell proliferation, survival, mobility and invasiveness in specific cancer cell types via signalization through PKC, ERK1/2, RhoGTPases, NFkappa-B, or focal adhesion kinase (FAK) activation (Leyton J et al, Eur J Pharmacol; 442(3):179-86, 2002; Ehlers R A et al Biochem Biophys Res Commun 269(3):704-8, 2000; Zhao D et al, Mol Pharmacol 67(6):2025-31, 2005). The NTS-NTSR1 complex was shown to be involved in tumor growth by disrupting the neurotensinergic pathway, via a specific antagonist, in experimental tumors generated in nude mice from colon, breast and small cell lung cancer cells, and thereby causing a strong reduction in tumor growth (Souaze F et al. Cancer Res 66(12):6243-9 2006, Moody T W et al Peptides 22(1):109-15, 2001; Maoret J J et al. Int J Cancer 80(3):448-54, 1999.
Non-small cell lung cancer is the leading cause of cancer-related deaths. The size of the primary tumor, the invasion of loco-regional nodes and, the presence of distant metastases, determine the survival rate. These parameters are used to define the stage of the disease and to decide the optimal patient management.
In spite of the progress in medical and surgical treatments, long term survival remains poor, with overall values ranging from 10 to 20% at 5 years. Chemotherapy has overall, a limited impact on survival either when used as an adjuvant treatment after surgery, or as a primary treatment in metastatic subjects. At present, the impact of molecular targeted drugs on the outcome of patients with lung cancer is also limited (Heasley L E. Oncogene 20(13):1563-9, 2001).
Operable patients have an overall 5-year survival rate around 40% and among them, those with stage I disease experience figures of only 60-70%. Identifying patients with pathologic initial stages but with a high risk of recurrence would be extremely useful, in order to individually tailor further management, in terms of more strict follow-up and/or adjuvant treatments (Scott W J et al, Chest. 2003 January; 123(1 Suppl):1885-201S).
Therefore, objects of the present invention are to provide methods for the treatment, the prognostic assessment and the staging of non-small cell lung cancer.